An enzymatic Alder-ene reaction

Masao Ohashi, Cooper S. Jamieson, Yujuan Cai, Dan Tan, Daiki Kanayama, Man-Cheng Tang, Sarah M. Anthony, Jason V. Chari, Joyann S. Barber, Elias Picazo, Thomas B. Kakule, Shugeng Cao, Neil K. Garg, Jiahai Zhou (), K. N. Houk () and Yi Tang ()
Additional contact information
Masao Ohashi: University of California, Los Angeles
Cooper S. Jamieson: University of California, Los Angeles
Yujuan Cai: University of Chinese Academy of Sciences
Dan Tan: University of California, Los Angeles
Daiki Kanayama: University of California, Los Angeles
Man-Cheng Tang: University of California, Los Angeles
Sarah M. Anthony: University of California, Los Angeles
Jason V. Chari: University of California, Los Angeles
Joyann S. Barber: University of California, Los Angeles
Elias Picazo: University of California, Los Angeles
Thomas B. Kakule: University of California, Los Angeles
Shugeng Cao: University of Hawaii at Hilo
Neil K. Garg: University of California, Los Angeles
Jiahai Zhou: University of Chinese Academy of Sciences
K. N. Houk: University of California, Los Angeles
Yi Tang: University of California, Los Angeles

Nature, 2020, vol. 586, issue 7827, 64-69

Abstract: Abstract An ongoing challenge in chemical research is to design catalysts that select the outcomes of the reactions of complex molecules. Chemists rely on organocatalysts or transition metal catalysts to control stereoselectivity, regioselectivity and periselectivity (selectivity among possible pericyclic reactions). Nature achieves these types of selectivity with a variety of enzymes such as the recently discovered pericyclases—a family of enzymes that catalyse pericyclic reactions1. Most characterized enzymatic pericyclic reactions have been cycloadditions, and it has been difficult to rationalize how the observed selectivities are achieved2–13. Here we report the discovery of two homologous groups of pericyclases that catalyse distinct reactions: one group catalyses an Alder-ene reaction that was, to our knowledge, previously unknown in biology; the second catalyses a stereoselective hetero-Diels–Alder reaction. Guided by computational studies, we have rationalized the observed differences in reactivities and designed mutant enzymes that reverse periselectivities from Alder-ene to hetero-Diels–Alder and vice versa. A combination of in vitro biochemical characterizations, computational studies, enzyme co-crystal structures, and mutational studies illustrate how high regioselectivity and periselectivity are achieved in nearly identical active sites.

Date: 2020
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DOI: 10.1038/s41586-020-2743-5

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